This project has addressed issues concerning a form of physiological synaptic plasticity in the hippocampus that is a promising candidate substrate mechanism for rapid associative conditioning, and currently the key preparation for studying the modifiability of mammalian central nervous system synapses. This activity-dependent phenomenon, termed associative long-term potentiation (LTP), has the following very interesting features: (a) it can be induced rapidly; (b) it is extremely persistent; (c) it may be induced in an associative manner; (d) it may be induced by activity paradigms analogous to differential conditioning; (e) it follows a Hebbian rule, requiring a conjunction of pre- and postsynaptic activity; (f) it occurs during short, bursts of stimulation that are modelled after hippocampal neuronal activity during certain behavioral states. The work in the present proposal will continue to examine the biophysical and biochemical mechanisms involved in the associative induction steps, and also continue to add to the list of associative capabilities of small networks of hippocampal neurons. We will use intracellular current- and voltage-clamp recording techniques in hippocampal slices as the primary experimental preparation and will specifically examine two second messenger systems to determine their possible role in mechanisms underlying the rapid-learning memory system, in which the hippocampus is thought to participate. One of these has been suggested to provide for control of synaptic function. Some questions will also be addressed at the molecular level by experiments on hippocampal postsynaptic receptor molecules that are expressed in oocytes. The results should bear directly on our understanding of the neurophysiology of memory, and indirectly on various neurological disorders of memory. In addition, the molecular mechanisms under study also appear to be involved in epilepsy, ischemic brain damage, and forms of developmental plasticity in other cortical regions.